Physical performance and plasma metabolic profile as potential prognostic factors in metastatic lung cancer patients.

BACKGROUND: Low physical performance is associated with higher mortality rate in multiple pathological conditions. Here, we aimed to determine whether body composition and physical performance could be prognostic factors in non-small cell lung cancer (NSCLC) patients. Moreover, we performed an exploratory approach to determine whether plasma samples from NSCLC patients could directly affect metabolic and structural phenotypes in primary muscle cells. METHODS: This prospective cohort study included 55 metastatic NSCLC patients and seven age-matched control subjects. Assessments included physical performance, body composition, quality of life and overall survival rate. Plasma samples from a sub cohort of 18 patients were collected for exploratory studies in cell culture and metabolomic analysis. RESULTS: We observed a higher survival rate in NSCLC patients with high performance in the timed up-and-go (+320%; p = .007), sit-to-stand (+256%; p = .01) and six-minute walking (+323%; p = .002) tests when compared to NSCLC patients with low physical performance. There was no significant association for similar analysis with body composition measurements (p > .05). Primary human myotubes incubated with plasma from NSCLC patients with low physical performance had impaired oxygen consumption rate (-54.2%; p < .0001) and cell proliferation (-44.9%; p = .007). An unbiased metabolomic analysis revealed a list of specific metabolites differentially expressed in the plasma of NSCLC patients with low physical performance. CONCLUSION: These novel findings indicate that physical performance is a prognostic factor for overall survival in NSCLC patients and provide novel insights into circulating factors that could impair skeletal muscle metabolism.

The Good, the Bad, and the Serum Creatinine: Exploring the Effect of Muscle Mass and Nutrition.

Muscle wasting (sarcopenia) is one of the hallmarks of critical illness. Patients admitted to intensive care unit develop sarcopenia through increased protein catabolism, a decrease in protein syntheses, or both. Among the factors known to promote wasting are chronic inflammation and cytokine imbalance, insulin resistance, hypermetabolism, and malnutrition. Moreover, muscle wasting, known to develop in chronic kidney disease patients, is a harmful consequence of numerous complications associated with deteriorated renal function. Plenty of published data suggest that serum creatinine (SCr) reflects increased kidney damage and is also related to body weight. Based on the concept that urea and creatinine are nitrogenous end products of metabolism, the urea:creatinine ratio (UCR) could be applied but with limited clinical usability in case of kidney damage, hypovolemia, excessive, or protein intake, where UCR can be high and independent of catabolism. Recent data suggest that the sarcopenia index should be considered an alternative to serum creatinine. It is more reliable in estimating muscle mass than SCr. However, the optimal biomarker of catabolism is still an unresolved issue. The SCr is not a promising biomarker for renal function and muscle mass based on the influence of several factors. The present review highlights recent findings on the limits of SCr as a surrogate marker of renal function and the assessment modalities of nutritional status and muscle mass measurements.

The Potential Modulatory Effects of Exercise on Skeletal Muscle Redox Status in Chronic Kidney Disease.

Chronic Kidney Disease (CKD) is a global health burden with high mortality and health costs. CKD patients exhibit lower cardiorespiratory and muscular fitness, strongly associated with morbidity/mortality, which is exacerbated when they reach the need for renal replacement therapies (RRT). Muscle wasting in CKD has been associated with an inflammatory/oxidative status affecting the resident cells' microenvironment, decreasing repair capacity and leading to atrophy. Exercise may help counteracting such effects; however, the molecular mechanisms remain uncertain. Thus, trying to pinpoint and understand these mechanisms is of particular interest. This review will start with a general background about myogenesis, followed by an overview of the impact of redox imbalance as a mechanism of muscle wasting in CKD, with focus on the modulatory effect of exercise on the skeletal muscle microenvironment.

Mitophagy-mediated inflammation and oxidative stress contribute to muscle wasting in cancer cachexia.

Cancer cachexia is commonly seen in patients with malignant tumors, which usually leads to poor life quality and negatively affects long-term prognosis and survival. Mitochondria dysfunction and enhanced autophagy are well-established to play an important role in skeletal muscle wasting. However, whether mitophagy is engaged in the pathogenesis of cancer cachexia requires further investigation. This study comprised a clinical study and animal experimentation. Clinical data such as CT images and laboratory results were obtained and analyzed. Then mice model of cancer cachexia and mitophagy inhibition were established. Data including skeletal muscle mass and function, mitochondria structure and function, inflammatory factors as well as ROS concentration. Mitophagy was enhanced in cancer cachexia patients with increased inflammatory factors. Greater disruption of skeletal muscle fiber and mitochondria structure were seen in cancer cachexia, with a higher level of inflammatory factors and ROS expression in skeletal muscle. Meanwhile, ATP production was undermined, indicating a close relationship with mitophagy, inflammation, and oxidative stress in the skeletal muscle of cancer cachexia mice models. In conclusion, mitophagy is activated in cancer cachexia and may play a role in skeletal muscle atrophy, and inflammation and oxidative stress might participate in mitophagy-related skeletal muscle injury.

Exogenous Melatonin Alleviates Skeletal Muscle Wasting by Regulating Hypothalamic Neuropeptides Expression in Endotoxemia Rats.

To investigate whether exogenous melatonin (MLT) could alleviate skeletal muscle wasting by regulating hypothalamic neuropeptides expression. Adult male Sprague Dawley rats were intraperitoneally injected with lipopolysaccharide (LPS) (10 mg/kg), followed by MLT (30 mg/kg/day) or saline for 3 days. Hypothalamic tissues and skeletal muscle were obtained on day 3. Skeletal muscle wasting was measured by the mRNA expression of two E3 ubiquitin ligases, muscle atrophy F-box and muscle ring finger 1 as well as 3-methylhistidine (3-MH) and tyrosine release. Three hypothalamic neuropeptides (POMC, AgRP, CART) expression were detected in all groups. POMC expression knockdown was achieved by ARC injection of lentiviruses containing shRNA against POMC. Two weeks after ARC viruses injection, rats were i.p. injected with LPS (10 mg/kg) followed by MLT (30 mg/kg/day) or saline for 3 days. Brain tissues were harvested for immunostaining. In septic rats, 3-MH, tyrosine release and muscle atrophic gene expression were significantly decreased in MLT treated group. POMC and CART expression were lower while AgRP expression was higher in MLT treated group. Furthermore, in septic rats treated with MLT, muscle wasting in those with lower expression of neuropeptide POMC did not differ from those with normal POMC expression. Exogenous MLT could alleviate skeletal muscle wasting in septic rats by regulating hypothalamic neuropeptides.

Transforming Growth Factor-Beta in Skeletal Muscle Wasting.

Transforming growth factor-beta (TGF-ß) is part of a family of molecules that is present in many body tissues and performs many different functions. Evidence has been obtained from mice and human cancer patients with bony metastases and non-metastatic disease, as well as pediatric burn patients, that inflammation leads to bone resorption and release of TGF-ß from the bone matrix with paracrine effects on muscle protein balance, possibly mediated by the generation of reactive oxygen species. Whether immobilization, which confounds the etiology of bone resorption in burn injury, also leads to the release of TGF-ß from bone contributing to muscle wasting in other conditions is unclear. The use of anti-resorptive therapy in both metastatic cancer patients and pediatric burn patients has been successful in the prevention of muscle wasting, thereby creating an additional therapeutic niche for this class of drugs. The liberation of TGF-ß may be one way in which bone helps to control muscle mass, but further investigation will be necessary to assess whether the rate of bone resorption is the determining factor for the release of TGF-ß. Moreover, whether different resorptive conditions, such as immobilization and hyperparathyroidism, also involve TGF-ß release in the pathogenesis of muscle wasting needs to be investigated.

The impact of skeletal muscle wasting during neoadjuvant chemotherapy on postoperative anastomotic leakage in patients with esophageal cancer.

BACKGROUND: Sarcopenia is defined by low muscle mass and low muscle strength and is a prognostic factor of unfavorable outcomes in various diseases. The purpose of this study is to examine the correlation between skeletal muscle wasting (SMW) during neoadjuvant chemotherapy (NAC) and postoperative complications in patients with esophageal cancer, particularly in relation to anastomotic leakage. METHODS: The present study involved 99 patients with thoracic esophageal cancer and esophago-gastric junctional cancer who received NAC followed by radical esophagectomy between August 2008 to June 2019, and who were pStage 0-III. Patient demographics and clinical variables were retrospectively reviewed. For assessing the extent of SMW, the rate of change in skeletal muscle mass index (SMI) was measured from CT images at the level of the third lumbar vertebra. Factors associated with postoperative complications were also examined. RESULTS: The median rate of change in total SMI in patients was - 1.87%. The decreased rates in SMI of the side abdominal muscles and rectus abdominis were significantly greater than that of the psoas major (side abdominal muscles: p = 0.0084, rectus abdominis: p = 0.036). Multivariate analysis showed a decreased rate in SMI, especially in the erector spinae muscle, and the Charlson comorbidity index (CCI) was significantly associated with Grade IIIa of higher anastomotic leakage (Grade ≥ IIIa) (SMI cutoff (favorable): ≤ - 7.84, p = 0.0040; CCI cutoff (favorable): ≥ 2, p = 0.0032). CONCLUSION: In patients with esophageal cancer, SMI tend to decrease during NAC treatment. It is therefore important to prevent the additional impact that SMW during NAC has on postoperative anastomotic leakage.

Skeletal muscle wasting in chronic kidney disease: the emerging role of microRNAs.

Skeletal muscle wasting is a common complication of chronic kidney disease (CKD), characterized by the loss of muscle mass, strength and function, which significantly increases the risk of morbidity and mortality in this population. Numerous complications associated with declining renal function and lifestyle activate catabolic pathways and impair muscle regeneration, resulting in substantial protein wasting. Evidence suggests that increasing skeletal muscle mass improves outcomes in CKD, making this a clinically important research focus. Despite extensive research, the pathogenesis of skeletal muscle wasting is not completely understood. It is widely recognized that microRNAs (miRNAs), a family of short non-coding RNAs, are pivotal in the regulation of skeletal muscle homoeostasis, with significant roles in regulating muscle growth, regeneration and metabolism. The abnormal expression of miRNAs in skeletal muscle during disease has been well described in cellular and animal models of muscle atrophy, and in recent years, the involvement of miRNAs in the regulation of muscle atrophy in CKD has been demonstrated. As this exciting field evolves, there is emerging evidence for the involvement of miRNAs in a beneficial crosstalk system between skeletal muscle and other organs that may potentially limit the progression of CKD. In this article, we describe the pathophysiological mechanisms of muscle wasting and explore the contribution of miRNAs to the development of muscle wasting in CKD. We also discuss advances in our understanding of miRNAs in muscle-organ crosstalk and summarize miRNA-based therapeutics currently in clinical trials.

Imperatorin alleviates cancer cachexia and prevents muscle wasting via directly inhibiting STAT3.

Skeletal muscle wasting is the most remarkable phenotypic feature of cancer cachexia that increases the risk of morbidity and mortality. Imperatorin (IMP), a main bioactive component of Angelica dahurica Radix, has been reported to possess several pharmacological effects including potential anti-colitis, anti-arthritis and anti-tumor activities. In this work, we demonstrated that IMP is a promising agent for the treatment of muscle wasting in cancer cachexia. IMP (5-20 µM) dose-dependently attenuated TCM-induced C2C12 myotube atrophy and prevented the induction of E3 ubiquitin ligases muscle RING-finger containing protein-1 (MuRF1) and muscle atrophy Fbox protein (Atrogin-1/MAFbx). Moreove, IMP administration significantly improved chief features of cancer cachexia in vivo, with significant prevention of the loss of body weight and deleterious wasting of multiple tissues, including skeletal muscle, fat and kidney and decreased expression of MuRF1 and Atrogin-1 in cachectic muscles. Cellular signaling pathway analysis showed that IMP selectively inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in vitro and in vivo, and surface plasmon resonance (SPR) affinity experiments further demonstrated IMP bound to STAT3 in a concentration-dependent resonance manner. Molecular docking results revealed that IMP binds to the SH2 domain of STAT3, forming a hydrogen bond interaction with Arg-609, and a Sigma-Pi interaction with Lys-591. Mechanism analysis demonstrated that STAT3 overexpression markedly weakens the improvements of IMP on myotube atrophy and muscle wasting of cancer cachexia, indicating that STAT3 mediated the therapeutic effect of IMP. All these favorable results indicated that IMP is a new potential therapeutic candidate for cancer cachexia.

CARM1 contributes to skeletal muscle wasting by mediating FoxO3 activity and promoting myofiber autophagy.

Coactivator-associated arginine methyltransferase 1 (CARM1) is involved in a variety of biological processes in different cell types and disease conditions, including myogenesis. However, the specific function of CARM1 in skeletal muscle wasting under pathologic conditions remains unclear. Here, we identify CARM1 as a novel participant in muscular atrophy. Increases in CARM1 protein levels correlated positively with the loss of muscle mass upon denervation in mice. Notably, the knockdown of CARM1 represses the progression of muscle wasting and the expression of the atrophy-related genes Atrogin-1 and MuRF1 in vivo and in vitro. With respect to the underlying mechanism, we show that CARM1 interacts with and asymmetrically dimethylates FoxO3 (a specific transcription factor that controls atrophy-related gene expression). This methylation modification by CARM1 is required for FoxO3-dependent transcription. Accordingly, a CARM1 methyltransferase inhibitor also restrains the expression of Atrogin-1 and MuRF1 and myotube atrophy. Furthermore, CARM1 knockdown induces a remarkable myofiber autophagic deficit during the atrophy process. Altogether, our study identifies a crucial regulator of skeletal muscle atrophy and suggests that CARM1 is a potential target for the prevention of muscle atrophy.

Omega-3 Fatty Acids-Enriched Fish Oil Activates AMPK/PGC-1α Signaling and Prevents Obesity-Related Skeletal Muscle Wasting.

Obesity is known to cause skeletal muscle wasting. This study investigated the effect and the possible mechanism of fish oil on skeletal muscle wasting in an obese rat model. High-fat (HF) diets were applied to induce the defects of lipid metabolism in male Sprague-Dawley rats with or without substitution of omega-3 fatty acids-enriched fish oil (FO, 5%) for eight weeks. Diets supplemented with 5% FO showed a significant decrease in the final body weight compared to HF diet-fed rats. The decreased soleus muscle weights in HF diet-fed rats could be improved by FO substitution. The decreased myosin heavy chain (a muscle thick filament protein) and increased FOXO3A and Atrogin-1 (muscle atrophy-related proteins) protein expressions in soleus muscles of HF diet-fed rats could also be reversed by FO substitution. FO substitution could also significantly activate adenosine monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation, peroxisome-proliferator-activated receptor-γ (PPARγ) coactivator 1α (PGC-1α), and PPARγ protein expression and lipoprotein lipase (LPL) mRNA expression in soleus muscles of HF diet-fed rats. These results suggest that substitution of FO exerts a beneficial improvement in the imbalance of lipid and muscle metabolisms in obesity. AMPK/PGC-1α signaling may play an important role in FO-prevented obesity-induced muscle wasting.

Clinical Response to Personalized Exercise Therapy in Heart Failure Patients with Reduced Ejection Fraction is Accompanied by Skeletal Muscle Histological Alterations.

Abstract: Heart failure (HF) is associated with skeletal muscle wasting and exercise intolerance. This study aimed to evaluate the exercise-induced clinical response and histological alterations. One hundred and forty-four HF patients were enrolled. The individual training program was determined as a workload at or close to the lactate threshold (LT1); clinical data were collected before and after 12 weeks/6 months of training. The muscle biopsies from eight patients were taken before and after 12 weeks of training: histology analysis was used to evaluate muscle morphology. Most of the patients demonstrated a positive response after 12 weeks of the physical rehabilitation program in one or several parameters tested, and 30% of those showed improvement in all four of the following parameters: oxygen uptake (VO2) peak, left ventricular ejection fraction (LVEF), exercise tolerance (ET), and quality of life (QOL); the walking speed at LT1 after six months of training showed a significant rise. Along with clinical response, the histological analysis detected a small but significant decrease in both fiber and endomysium thickness after the exercise training course indicating the stabilization of muscle mechanotransduction system. Together, our data show that the beneficial effect of personalized exercise therapy in HF patients depends, at least in part, on the improvement in skeletal muscle physiological and biochemical performance.

Growth Hormone Secretagogues and the Regulation of Calcium Signaling in Muscle.

Growth hormone secretagogues (GHS) are a family of synthetic molecules, first discovered in the late 1970s for their ability to stimulate growth hormone (GH) release. Many effects of GHS are mediated by binding to GHS-R1a, the receptor for the endogenous hormone ghrelin, a 28-amino acid peptide isolated from the stomach. Besides endocrine functions, both ghrelin and GHS are endowed with some relevant extraendocrine properties, including stimulation of food intake, anticonvulsant and anti-inflammatory effects, and protection of muscle tissue in different pathological conditions. In particular, ghrelin and GHS inhibit cardiomyocyte and endothelial cell apoptosis and improve cardiac left ventricular function during ischemia-reperfusion injury. Moreover, in a model of cisplatin-induced cachexia, GHS protect skeletal muscle from mitochondrial damage and improve lean mass recovery. Most of these effects are mediated by GHS ability to preserve intracellular Ca2+ homeostasis. In this review, we address the muscle-specific protective effects of GHS mediated by Ca2+ regulation, but also highlight recent findings of their therapeutic potential in pathological conditions characterized by skeletal or cardiac muscle impairment.

MicroRNA-542 Promotes Mitochondrial Dysfunction and SMAD Activity and Is Elevated in Intensive Care Unit-acquired Weakness.

RATIONALE: Loss of skeletal muscle mass and function is a common consequence of critical illness and a range of chronic diseases, but the mechanisms by which this occurs are unclear. OBJECTIVES: To identify microRNAs (miRNAs) that were increased in the quadriceps of patients with muscle wasting and to determine the molecular pathways by which they contributed to muscle dysfunction. METHODS: miRNA-542-3p/5p (miR-542-3p/5p) were quantified in the quadriceps of patients with chronic obstructive pulmonary disease and intensive care unit-acquired weakness (ICUAW). The effect of miR-542-3p/5p was determined on mitochondrial function and transforming growth factor-ß signaling in vitro and in vivo. MEASUREMENTS AND MAIN RESULTS: miR-542-3p/5p were elevated in patients with chronic obstructive pulmonary disease but more markedly in patients with ICUAW. In vitro, miR-542-3p suppressed the expression of the mitochondrial ribosomal protein MRPS10 and reduced 12S ribosomal RNA (rRNA) expression, suggesting mitochondrial ribosomal stress. miR-542-5p increased nuclear phospho-SMAD2/3 and suppressed expression of SMAD7, SMURF1, and PPP2CA, proteins that inhibit or reduce SMAD2/3 phosphorylation, suggesting that miR-542-5p increased transforming growth factor-ß signaling. In mice, miR-542 overexpression caused muscle wasting, and reduced mitochondrial function, 12S rRNA expression, and SMAD7 expression, consistent with the effects of the miRNAs in vitro. Similarly, in patients with ICUAW, the expression of 12S rRNA and of the inhibitors of SMAD2/3 phosphorylation were reduced, indicative of mitochondrial ribosomal stress and increased transforming growth factor-ß signaling. In patients undergoing aortic surgery, preoperative levels of miR-542-3p/5p were positively correlated with muscle loss after surgery. CONCLUSIONS: Elevated miR-542-3p/5p may cause muscle atrophy in intensive care unit patients through the promotion of mitochondrial dysfunction and activation of SMAD2/3 phosphorylation.

Significance of Sarcopenia Evaluation in Acute Decompensated Heart Failure.

In patients with chronic heart failure (HF), the clinical importance of sarcopenia has been recognized in relation to disease severity, reduced exercise capacity, and adverse clinical outcome. Nevertheless, its impact on acute decompensated heart failure (ADHF) is still poorly understood. Dual-energy X-ray absorptiometry (DXA) is a technique for quantitatively analyzing muscle mass and the degree of sarcopenia. Fat-free mass index (FFMI) is a noninvasive and easily applicable marker of muscle mass.This was a prospective observational cohort study comprising 38 consecutive patients hospitalized for ADHF. Sarcopenia, derived from DXA, was defined as a skeletal muscle mass index (SMI) two standard deviations below the mean for healthy young subjects. FFMI (kg/m2) was calculated as 7.38 + 0.02908 × urinary creatinine (mg/day) divided by the square of height (m2).Sarcopenia was present in 52.6% of study patients. B-type natriuretic peptide (BNP) levels were significantly higher in ADHF patients with sarcopenia than in those without sarcopenia (1666 versus 429 pg/mL, P < 0.0001). Receiver operator curves were used to compare the predictive accuracy of SMI and FFMI for higher BNP levels. Areas under the curve for SMI and FFMI were 0.743 and 0.717, respectively. Multiple logistic regression analysis showed sarcopenia as a predictor of higher BNP level (OR = 18.4; 95% CI, 1.86-181.27; P = 0.013).Sarcopenia is associated with increased disease severity in ADHF. SMI based on DXA is potentially superior to FFMI in terms of predicting the degree of severity, but FFMI is also associated with ADHF severity.

The TGF-ß Signalling Network in Muscle Development, Adaptation and Disease.

Skeletal muscle possesses remarkable ability to change its size and force-producing capacity in response to physiological stimuli. Impairment of the cellular processes that govern these attributes also affects muscle mass and function in pathological conditions. Myostatin, a member of the TGF-ß family, has been identified as a key regulator of muscle development, and adaptation in adulthood. In muscle, myostatin binds to its type I (ALK4/5) and type II (ActRIIA/B) receptors to initiate Smad2/3 signalling and the regulation of target genes that co-ordinate the balance between protein synthesis and degradation. Interestingly, evidence is emerging that other TGF-ß proteins act in concert with myostatin to regulate the growth and remodelling of skeletal muscle. Consequently, dysregulation of TGF-ß proteins and their associated signalling components is increasingly being implicated in muscle wasting associated with chronic illness, ageing, and inactivity. The growing understanding of TGF-ß biology in muscle, and its potential to advance the development of therapeutics for muscle-related conditions is reviewed here.

Progressive Resistance Exercise Training in CKD: A Feasibility Study.

BACKGROUND: Skeletal muscle wasting in chronic kidney disease (CKD) is associated with morbidity and mortality. Resistance exercise results in muscle hypertrophy in the healthy population, but is underinvestigated in CKD. We aimed to determine the feasibility of delivering a supervised progressive resistance exercise program in CKD, with secondary aims to investigate effects on muscle size, strength, and physical functioning. STUDY DESIGN: Parallel randomized controlled feasibility study. SETTING & PARTICIPANTS: Patients with CKD stages 3b to 4 were randomly assigned to the exercise (n=20; 11 men; median age, 63 [IQR, 57-65] years; median estimated glomerular filtration rate, 28.5 [IQR, 19.0-32.0] mL/min/1.73 m(2)) or nonexercise control (n=18; 14 men; median age, 66 [IQR, 45-79] years; estimated glomerular filtration rate, 20.5 [IQR, 16.0-26.0] mL/min/1.73 m(2)) group. INTERVENTION: Patients in the exercise group undertook an 8-week progressive resistance exercise program consisting of 3 sets of 10 to 12 leg extensions at 70% of estimated 1-repetition maximum thrice weekly. Patients in the control group continued with usual physical activity. OUTCOMES: Primary outcomes were related to study feasibility: eligibility, recruitment, retention, and adherence rates. Secondary outcomes were muscle anatomical cross-sectional area, muscle volume, pennation angle, knee extensor strength, and exercise capacity. MEASUREMENTS: Two- and 3-dimensional ultrasonography of skeletal muscle, dynamometry, and shuttle walk tests at baseline and 8 weeks. RESULTS: Of 2,349 patients screened, 403 were identified as eligible and 38 enrolled in the study. 33 (87%) completed the study, and those in the exercise group attended 92% of training sessions. No changes were seen in controls for any parameter. Progressive resistance exercise increased muscle anatomical cross-sectional area, muscle volume, knee extensor strength, and exercise capacity. LIMITATIONS: No blinded assessors, magnetic resonance imaging not used to assess muscle mass, lack of a healthy control group. CONCLUSIONS: This type of exercise is well tolerated by patients with CKD and confers important clinical benefits; however, low recruitment rates suggest that a supervised outpatient-based program is not the most practical implementation strategy.

Analysis of MicroRNA Expression Profiles in Weaned Pig Skeletal Muscle after Lipopolysaccharide Challenge.

MicroRNAs (miRNAs) constitute a class of non-coding RNAs that play a crucial regulatory role in skeletal muscle development and disease. Several acute inflammation conditions including sepsis and cancer are characterized by a loss of skeletal muscle due primarily to excessive muscle catabolism. As a well-known inducer of acute inflammation, a lipopolysaccharide (LPS) challenge can cause serious skeletal muscle wasting. However, knowledge of the role of miRNAs in the course of inflammatory muscle catabolism is still very limited. In this study, RNA extracted from the skeletal muscle of pigs injected with LPS or saline was subjected to small RNA deep sequencing. We identified 304 conserved and 114 novel candidate miRNAs in the pig. Of these, four were significantly increased in the LPS-challenged samples and five were decreased. The expression of five miRNAs (ssc-miR-146a-5p, ssc-miR-221-5p, ssc-miR-148b-3p, ssc-miR-215 and ssc-miR-192) were selected for validation by quantitative polymerase chain reaction (qPCR), which found that ssc-miR-146a-5p and ssc-miR-221-5p were significantly upregulated in LPS-challenged pig skeletal muscle. Moreover, we treated mouse C2C12 myotubes with 1000 ng/mL LPS as an acute inflammation cell model. Expression of TNF-α, IL-6, muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MuRF1) mRNA was strongly induced by LPS. Importantly, miR-146a-5p and miR-221-5p also showed markedly increased expression in LPS-treated C2C12 myotubes, suggesting the two miRNAs may be involved in muscle catabolism systems in response to acute inflammation caused by a LPS challenge. To our knowledge, this study is the first to examine miRNA expression profiles in weaned pig skeletal muscle challenged with LPS, and furthers our understanding of miRNA function in the regulation of inflammatory muscle catabolism.

Nocturnal Hypoxemia Is Associated with Sarcopenia in Patients with Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. Our previous studies have identified that nocturnal hypoxemia causes skeletal muscle loss (i.e., sarcopenia) in in vitro models of COPD. Objectives: We aimed to extend our preclinical mechanistic findings by analyzing a large sleep registry to determine whether nocturnal hypoxemia is associated with sarcopenia in patients with COPD. Methods: Sleep studies from patients with COPD (n = 479) and control subjects without COPD (n = 275) were analyzed. Patients with obstructive sleep apnea, as defined by apnea-hypopnea index ⩾ 5, were excluded. Pectoralis muscle cross-sectional area (PMcsa) was quantified using computed tomography scans performed within 1 year of the sleep study. We defined sarcopenia as less than the lowest 20% residuals for PMcsa of control subjects, which was adjusted for age and body mass index (BMI) and stratified by sex. Youden's optimal cut-point criteria were used to predict sarcopenia based on mean oxygen saturation during sleep. Additional measures of nocturnal hypoxemia were analyzed. The pectoralis muscle index (PMI) was defined as PMcsa normalized to BMI. Results: On average, males with COPD had a 16.6% lower PMI than control males (1.41 ± 0.44 vs. 1.69 ± 0.56 cm2/BMI; P < 0.001), whereas females with COPD had a 9.4% lower PMI than control females (0.96 ± 0.27 vs. 1.06 ± 0.33 cm2/BMI; P < 0.001). Males with COPD with nocturnal hypoxemia had a 9.5% decrease in PMI versus COPD with normal O2 (1.33 ± 0.39 vs. 1.47 ± 0.46 cm2/BMI; P < 0.05) and a 23.6% decrease compared with control subjects (1.33 ± 0.39 vs. 1.74 ± 0.56 cm2/BMI; P < 0.001). Females with COPD with nocturnal hypoxemia had an 11.2% decrease versus COPD with normal O2 (0.87 ± 0.26 vs. 0.98 ± 0.28 cm2/BMI; P < 0.05) and a 17.9% decrease compared with control subjects (0.87 ± 0.26 vs. 1.06 ± 0.33 cm2/BMI; P < 0.001). These findings were largely replicated using multiple measures of nocturnal hypoxemia. Conclusions: We defined sarcopenia in the pectoralis muscle using residuals that take into account age, BMI, and sex. We found that patients with COPD have a lower PMI than patients without COPD and that nocturnal hypoxemia was associated with an additional decrease in the PMI of patients with COPD. Additional prospective analyses are needed to determine a protective threshold of oxygen saturation to prevent or reverse sarcopenia due to nocturnal hypoxemia in COPD.